Complete resolution of pain (≥1-month pain-free interval between the diagnoses of AP) OR

Complete normalization of serum pancreatic enzyme levels (amylase and lipase), before the subsequent episode of AP is diagnosed, along with complete resolution of pain symptoms, irrespective of a specific time interval between AP episodes

Epidemiology

About 11,000, 13 cases per 100,000, children present with AP in the US annually, with inpatient costs alone in excess of $200 million per year. As with adults, multiple studies have shown the incidence to be increasing dramatically over the past 15 years. The reasons are not entirely clear, but may include changing trends in etiology, increased referral to academic centers where trends are reported, and increased use of diagnostic testing.

Aggregated etiologies of AP. Adapted from Table 4, Bai, et al.

Acute Pancreatitis - Pathophysiology

Acute pancreatitis is a reversible process characterized by the presence of interstitial edema, infiltration by acute inflammatory cells, and varying degrees of necrosis, apoptosis, and hemorrhage.

Current science supports multiple etiologies that converge on one common biochemical pathway. Broadly, acinar cell injury (drugs, metabolic disorders, infection), obstruction of ductal flow (structural), or failure in feedback control (hereditary) are important initiators.

Aberrant, non-physiological calcium signals are generated within the pancreatic acinar cells, leading to premature activation of intraacinar pancreatic proenzymes. These activated zymogens, particularly trypsin, effect cell injury and lead to production of cytokines that stimulate an inflammatory reaction.

Local apoptosis and necrosis occur, but it is the acute inflammatory response that is often most problematic; when marked, it can develop into systemic inflammatory response syndrome (SIRS).

The pancreas is endowed with several protective mechanisms that must be overcome by this process. These mechanisms include compartmentalization of pancreatic enzymes, the presence of trypsin inhibitors, and autodegradation of trypsin.

Acute Pancreatitis - Diagnosis

Clinically, there is large variance in the presentation between children of different ages. One retrospective study of 271 patients by Park et al showed that infants and toddlers manifested fewer signs and symptoms of abdominal pain, epigastric tenderness, and nausea/vomiting.

Below are the percentages per age group with
presenting with the complaint

Age

0-2y

3-10

11-20

Total Cohort

Abdominal pain

42.9%

93.2%

93.4%

90%

Epigastric tenderness

57.1%

86.4%

87.2%

85%

Nausea/vomiting

28.6%

69.5%

78.1%

73%

Adapted from Table 1 of Park et al.

Biochemically, amylase and lipase values greater than 3x the normal limits are used.

In Park et al, peak lipase levels were elevated in all patients, however, in ages 0-2, amylase levels were elevated in only 66% (similar non-significant trends were noted in the other age cohorts). However, there have also been numerous case reports showing elevations in only the amylase at time of diagnosis. It is important to note that numerous illnesses can cause elevation of one or both of these enzymes.

Radiographically, ultrasound is generally most appealing as an initial imaging tool, as it is widely available and avoids radiation exposure. It also has the benefit of quickly evaluating for other causes of an acute abdomen and allowing for detection of gallstones that may be causing the pancreatitis. Disadvantages include operator dependence and obscured imaging in the presence of overlying bowel gas or obesity. Diagnostic features include pancreatic heterogeneity, edema, and peripancreatic fluid collections.

CT is generally not recommended to evaluate patients on initial presentation, unless the diagnosis is unclear, due to low sensitivity and concerns over radiation. It is more often used further into the course, when pancreatic necrosis is suspected clinically. Diagnostic features include parenchymal changes and peripancreatic fluid.

Acute Pancreatitis - Course/Management

The median length of hospitalization is 5-8 days. While making patients NPO has been a tenet of treatment for many years, more recent studies in adults have shown that early enteral feeding reduces complications of acute pancreatitis. Current guidelines generally recommend jejunal feeding within 1 to 2 days of developing severe pancreatitis, with a possible role for slow, continuous nasogastric tube feeds.

In patients with mild AP, two RCTs have shown that providing a soft, low-fat diet rather than a clear liquid diet reduces length of hospitalization.

Early, aggressive intravenous fluid resuscitation is also accepted, but the optimal rate, type, and volume remains unknown. Younger patients may benefit from a GI consult, as many pediatricians are uncomfortable managing AP in this demographic. Additionally, the Ranson, PAPS, and modified Glasgow scores may be used to predict patient course, but are often not accurate enough to be of great clinical utility.

Late complications include pancreatic necrosis and pseudocyst formation. Necrotic tissue can form walled-off fluid collections and can also be complicated by the presence of infection. A pseudocyst is defined as a homogeneous collection of amylase-rich pancreatic fluid that lacks an epithelium.

In general, asymptomatic pseudocysts can be managed conservatively. Indications for drainage include complications such as bleeding or infection, though recent data has shown that FNA can be falsely negative and that debridement of sterile, well-demarcated pancreatic necrosis may be associated with lower mortality.

Fewer than 6% of children went on to develop multi-organ dysfunction or pancreatic necrosis. Pseudocysts formed in 10-20% of patients and were associated with trauma. About 15-35% of children developed recurrent pancreatitis, with one study showing an average of 2.7 episodes for patients, with fewer recurrences noted in infants. Mortality ranged from 0-11%.

Chronic Pancreatitis - Epidemiology

Little is known about the epidemiology of chronic pancreatitis in children. The prevalence is less than that of acute pancreatitis, but the incidence may be increasing.

Chronic Pancreatitis - Etiology

Chronic pancreatitis in children has a variety of causes, some of which are present throughout life, but not often diagnosed until adulthood.

Chronic pancreatitis in childhood, adapted from Nydegger et al.

Cystic fibrosis

Fibrosing pancreatitis

Hereditary chronic pancreatitis

Inborn errors of metabolism (esp. branched chain aminoacidemias)

Idiopathic

Chronic hereditary pancreatitis (usually diagnosed as an adult)

Hyperlipidemias

Partial lipodystrophy

Wilson's disease

Hemochromatosis

Alpha-1 antitrypsin deficiency

Chronic Pancreatitis - Pathophysiology

Chronic pancreatitis is an inflammatory disorder that is characterized by chronic inflammatory cell infiltration and changes that include parenchymal fibrosis. The changes are irreversible and ultimately leads to a decline in exocrine and endocrine function.

Functional insufficiency in endocrine (e.g. diabetes) and exocrine (e.g. steatorrhea) generally are noted to become noticeable when 90% or more of the cells are destroyed.

In the past, hypotheses have included the necrosis-fibrosis hypothesis, whereby CP results as a result of repeated episodes of acute inflammation. However, this does not explain why some patients with hereditary or alcoholic pancreatitis progress to a chronic process without evidence of significant necrosis.

Whitcomb has proposed a sentinel acute pancreatitis event (SAPE). The sentinel event must be sufficiently severe to attract monocytes and cause infiltration, differentiation, and proliferation of pancreatic stellate cells. For fibrosis to occur, the injury must also be recurrent , so as to create an appropriate chemocytokine milieu for the continuing stimulation of the stellate cells. Ultimately, the changes are likely to be mediated through the single common pathway described above under acute pancreatitis.

Chronic Pancreatitis - Diagnosis

Again, because biopsy is both impractical and potentially dangerous in many patients, the clinical, laboratory, and radiologic criteria listed above are essential for diagnosis.

Clinically, abdominal pain, weight loss, diabetes mellitus, and malabsorption may be noted. The pain is commonly described as epigastric, deep or penetrating toward the back, accompanied by nausea and vomiting, relieved by sitting forward, and may be exacerbated post-prandially. While there is inter-person variability in the intermittency of the pain, there is a tendency for the pain to burn out.

Exocrine insufficiency is characterized by bulky and oily stools accompanied by weight loss, while endocrine insufficiency is characterized by diabetes mellitus. In adults, exocrine insufficiency occurred in 50-80% of patients at a median of 5.6-13.1 years, while endocrine insufficiency occurred in 40-70% of patients at a median of 11.9 to 26.3 years.

Laboratory testing can be broken down into direct and indirect testing. Direct tests include small intestinal intubation, using exogenous hormonal stimulants (secretin and CCK) or nutrient stimulants to measure secretory capacity. These tests are highly sensitive and specific, but time-consuming and invasive.

Indirect tests detect abnormalities secondary to loss of pancreatic function, such as stool microscopy for fat globules and assays for fecal elastase, as well as other stool, breath, and urine/plasma tests. However, these tests tend to lack both sensitivity and specificity and cannot distinguish between mild and moderate exocrine function. Nydegger et al believe that the use of fecal elastase and a 72h fecal fat balance is adequate for most children.

US, CT, Endoscopic Retrograde Cholangiopancreatography (ERCP), and Magnetic Resonance Cholangiopancreatography (MRCP) are utilized. US findings include dilation of the pancreatic duct, ductal stones, irregularities in gland margins/changes in echotexture, and the presence of pseudocysts. The sensitivity is about 50-80% with a specificity of 90%.

Endoscopic ultrasound showed agreement with ERCP, the gold standard, in 75% of cases.

This test is subjective, shows substantial intra- and inter-observer variability, and may confuse changes of AP for CP.

CT is both highly sensitive and specific, but carries the concomitant risk of radiation exposure. Findings include ductal or parenchymal calcifications, dilation of the main ducts, and pancreatic atrophy.

MRCP is an evolving tool that is non-invasive, without radiation, and provides comprehensive ductal morphology in the normal, physiologic state (as opposed to under pressure in ERCP). Secretin can be used to further enhance visualization of the smaller ducts. Limitations occur with small-caliber, non-dilated ducts, poor signal, and patient motion.

In children with evidence of chronic pancreatitis, Nydegger et al suggested the following tests:

Sweat test

Gene testing for CFTR

Ctionic trypsinogen and SPINK 1 mutations

Imaging to exclude a structural (congenital or acquired) etiology

Assessment for auto-immune causes.

Chronic Pancreatitis - Course/management

In patients with chronic pancreatitis, there are multiple goals to be pursued. First, every effort should be made to establish a strong diagnosis and etiology. Second, adequate analgesia must be attained. Third, long-term follow-up with close attention to monitoring and treatment of exocrine insufficiency and diabetes mellitus is essential. Fourth, patients should be educated to avoid smoking and alcohol, which increase their risk of pancreatic adenocarcinoma.

Other treatments that have been advocated include antioxidants, pancreatic enzyme replacement, octreotide, and pancreatic protease inhibitors. However, there is currently insufficient evidence to recommend the use of any of these treatments.

Finally, surgery is usually only indicated when there is chronic, unremitting pain unresponsive to medical treatment. The principal goal of intervention is provision of adequate drainage of the pancreatic ducts. The procedures can be done endoscopically or surgically. Pancreatic resections are associated with high morbidity and mortality and rarely required.